The existence of multiple conformers of interleukin-21 directs engineering of a superpotent analogue
The existence of multiple conformers of interleukin-21 directs engineering of a superpotent analogue
复制标题
DOI：
10.1074/jbc.m701313200
复制
发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Hjorth, Siv A.
中科院分区：
文献类型：
--
作者：
Bondensgaard, Kent;Breinholt, Jens;Hjorth, Siv A.
用核磁共振波谱法研究了人白细胞介素-21（hIL-21）的高分辨三维结构。总的来说，hIL-21结构主要由一个明确的中央四螺旋束，排列在一个向上-向上-向下-向下的拓扑结构，如观察到的其他细胞因子。观察到包括第三螺旋段螺旋C的hIL-21分子的一段以两种不同且可互换的状态存在。在一种构象异构体中，螺旋C片段以规则的α-螺旋构象存在，而在另一种构象异构体中，该片段在很大程度上是无序的。基于结构的序列比对hIL-21与相关细胞因子，白细胞介素-2和-4的受体复合物，这意味着这一特定的片段参与受体结合。设计hIL-21类似物以通过引入从hIL-4接枝的片段来稳定螺旋C周围的区域。这种新的hIL-21类似物被证明在细胞测定中表现出10倍的效力增加。
The high resolution three-dimensional structure of human interleukin (hIL)-21 has been resolved by heteronuclear NMR spectroscopy. Overall, the hIL-21 structure is dominated by a well defined central four-helical bundle, arranged in an up-up-down-down topology, as observed for other cytokines. A segment of the hIL-21 molecule that includes the third helical segment, helix C, is observed to exist in two distinct and interchangeable states. In one conformer, the helix C segment is presented in a regular, alpha-helical conformation, whereas in the other conformer, this segment is largely disordered. A structure-based sequence alignment of hIL-21 with receptor complexes of the related cytokines, interleukin-2 and -4, implied that this particular segment is involved in receptor binding. An hIL-21 analog was designed to stabilize the region around helix C through the introduction of a segment grafted from hIL-4. This novel hIL-21 analog was demonstrated to exhibit a 10-fold increase in potency in a cellular assay.